chr2-46329206-G-A

Variant names:

• chr2-46329206-G-A
• rs13419896
• NM_001430.5:c.27-17667G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001430.5(EPAS1):​c.27-17667G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,168 control chromosomes in the GnomAD database, including 1,517 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (1517 hom., cov: 32)
• Consequence: EPAS1 NM_001430.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.188
• Publications: 31 publications found

Genes affected

EPAS1 (HGNC:3374): (endothelial PAS domain protein 1) This gene encodes a transcription factor involved in the induction of genes regulated by oxygen, which is induced as oxygen levels fall. The encoded protein contains a basic-helix-loop-helix domain protein dimerization domain as well as a domain found in proteins in signal transduction pathways which respond to oxygen levels. Mutations in this gene are associated with erythrocytosis familial type 4. [provided by RefSeq, Nov 2009]

EPAS1 Gene-Disease associations (from GenCC):

• erythrocytosis, familial, 4

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• autosomal dominant secondary polycythemia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.281 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001430.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	NM_001430.5	MANE Select	c.27-17667G>A		intron	N/A	NP_001421.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPAS1	ENST00000263734.5	TSL:1 MANE Select	c.27-17667G>A		intron	N/A	ENSP00000263734.3	Q99814
	EPAS1	ENST00000861819.1		c.27-17667G>A		intron	N/A	ENSP00000531878.1
	EPAS1	ENST00000861817.1		c.27-17673G>A		intron	N/A	ENSP00000531876.1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15438 AN: 152050 Hom.: 1519 Cov.: 32

Gnomad AFR AF: 0.234

Gnomad AMI AF: 0.120

Gnomad AMR AF: 0.0484

Gnomad ASJ AF: 0.0726

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0595

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0226

Gnomad OTH AF: 0.0736

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.102 AC: 15458 AN: 152168 Hom.: 1517 Cov.: 32 AF XY: 0.105 AC XY: 7826 AN XY: 74392

African (AFR) AF: 0.234 AC: 9692 AN: 41462

American (AMR) AF: 0.0486 AC: 744 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0726 AC: 252 AN: 3470

East Asian (EAS) AF: 0.294 AC: 1518 AN: 5170

South Asian (SAS) AF: 0.170 AC: 820 AN: 4824

European-Finnish (FIN) AF: 0.0595 AC: 631 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0226 AC: 1536 AN: 68010

Other (OTH) AF: 0.0733 AC: 155 AN: 2114

Alfa AF: 0.0429 Hom.: 181

Bravo AF: 0.107

Asia WGS AF: 0.212 AC: 739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	3.1
DANN	Benign	0.60
PhyloP100		-0.19
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13419896; hg19: chr2-46556345;